Diagnosis of Noise-Induced Hidden Hearing Loss Summary Recent research has demonstrated that although a short-term exposure to moderate levels of noise does not cause apparent hair cell loss, it can induce irreversible auditory nerve degeneration, in particular, loss of low spontaneous rate (LSR) auditory neurons and their synapses with inner hair cells. This may eventually result in difficulty hearing speech in noisy environments. Unfortunately, such hearing loss and synaptopathy are not readily detectable by current clinical auditory tests, leading to ?hidden? hearing loss (HLL). The goal of this project is to develop a simple, clinically- feasible method to diagnose such cochlear synaptopathy and associated HHL in humans. Auditory nerves can be divided into three groups based on their spontaneous discharge rates. Medium and high spontaneous rate (M/HSR) fibers have low-threshold but their discharges are quickly saturated as sound intensity increases, whereas LSR fibers have high threshold and their discharge rates can still increase at high-intensity levels. However, most routine audiological measures are based on gross threshold detection. Thus, these tests mainly reflect M/HSR fiber function and thereby miss LSR fiber impairment leading to HHL. In this study, we hypothesize that if we use a moderate level of noise to mask or saturate M/HSR fibers, only the LSR fibers are activated. Thus, LSR fiber function and impairment can be detected. That is, the measured threshold of auditory brainstem response (ABR) or auditory nerve compound action potential (CAP) responses under such conditional noise masking (CNM) will mainly reflect LSR fiber activity and function. Moreover, if the LSR fibers are damaged or degenerated, the measured CNM ABR thresholds or CAP thresholds will be substantially increased in comparison with those in the normal group without noise-exposure. Since human auditory nerve histopathology analysis is not possible in life, we will first test whether this simple but novel CNM method can detect noise-induced HHL and synaptopathy in mice (Specific Aim 1), in which auditory nerve and synapse degeneration can be directly assessed with morphological examinations. Thus, the direct link between the diagnosis and the underlying cochlear synaptopathy can be established and verified. Then, we will apply this CNM method to humans to test whether it can detect noise-induced HHL (Specific Aim 2). Combined with behavioral audiological tests, we will further assess perceptual function to investigate if the cochlear synaptopathy induces poor speech-in-noise ability in the central auditory system. Undoubtedly, completion of these studies will provide a novel, clinically-feasible auditory test to diagnose noise-induced HHL. This technique may also provide an early diagnosis of age-induced hearing loss, since it may share common and similar neuropathy and synaptopathy with noise-induced HHL, in particular, in its early stage.